Sulfur-containing naphthoquinones



United States Patent ce Patented Oct. 25, 1966 takes place at room temperature but can be carried out 3,281,422 partially or entirely at temperatures somewhat above or SULFUR-CONTAINING NAPHTHOQUINONES somewhat below room temperature depending upon the Walter Gauss, Cologne-Stammheim, Karl-Wolfgang particular reactants employed. The reaction may also be schenhammer' Leverkusen and Marla Bmmmelhues 5 carried out in the presence of a solvent or diluent and for Wuppertal-Sonnborn, Germany, asslgnors t0 Farbenthat purpose lower aliphatic alcohols such as methanol 22;??? f zfig z i g gfgiig Leverkusen Ger and ethanol have been found to be very suitable but other N0 Drawing Filed Jam 15 19 4 S 337,731 inert solvents can also be employed. The reactions give 6 Claims. (Cl. 260-268) excellent yields and the reaction products are, for the most 10 part, crystalline compounds which either as such or in The present invention relates to novel chemi al comthe form of the usual pharmaceutically acceptable nonpounds useful for inhibiting or retarding growth or multitoxic salts such as the hydrochloride have eifective action plication of microorganisms including bacteria and more in checking or stopping the growth of microorganisms.

particularly to sulfur-containing naphthoquinones which Among the haloalkylated naphthoquinones which can are the reaction products of haloalkylated naphthobe used are 2-methyl-3-chloromethyl-1,4-naphthoquinone,

quinones and mercapto or mercapto-like compounds. 2,3-bis-chloromethyl-1,4-naphthoquinone and 2 methyl- This application is a continuation-in-part of United States 3-(wbromoethyl) 1,4 naphthoquinone. The haloalkyl- Serial No. 188,248, filed April 17, 1962, now abandoned. ated naphthoquinone is reacted either as such or in the The compounds of the invention have the formula: form of its alkali metal salt, e.g. the sodium or potassium salt with, for instance, potassium Xanthate, potassium II 0,0-diethyl thiono thiolphosphate, thiourea, potassium R1 N,N-pentamethylene dithiocarbamate with pipenidine and carbon disulfide, sodium N,N-pentamethylene dithiocarbamate with piperidine and carbon disulfide, 0,0-diethyl thiono thiol-phosphori-c acid potassium salt, N-aminoo morpholine and carbon disulfide or N-methylpiperazine in which R1 is Selected from the group consisting of and carbon disulfide. In general the haloalkylated naphthoquinone is reacted with the merca-pto or mercapto-like CH3 compound in such proportions that for each haloalkyl s group there is preferably used one mole of an alkali ll metal or ammonium salt of the mercapto or mercaptolike compound which may, however, be present in slight s excess. {L The novel compounds of the present invention as set forth in the following examples represent an outstanding F group of compounds with excellent antimicrobial activ- Om-s-d ity. The new compounds may be administered or applied NH: in any suitable dosage form in conjunction with any of the usual vehicles or carriers.

ll s O CHTST% N /NCH3 To a suspension of 55 g. (0.25 mole) of 2-methyl-3- s chloromethyl-1,4-naphthoquinone in 500 ml. of alcohol nd R i selected from the group consisting of there is added dropwise with stirring a solution of 48 g.

CH3 (0.30 mole) of potassium xanthate in 1.25 liters of alcohol. The yellow reaction product precipitates in the CHg-SCOC2H5 course of the reaction. After stirring for a further 15 g minutes the product is filtered oil with suction at 0 C., washed successively with alcohol, water and alcohol and oHzs-P( CiHs)z dried. The product (69.9 g. of MP. 96-97 C.) can be g obtained analytically pure by recrystallizing from ten times its quantity of alcohol and then melts at 9899 C. OHzS-CNH2 Example 2 1 s o1nsfi-N ctaakoaa S l If It... and r-S |T-O 2 s oH-sI -(oo2n5 2 l 8 S To a suspension consisting of 12.8 g. of 2,3-bis-chloro- R and R never both being CH 7O methyl-1,4-naphthoquinone and 100 ml. of alcohol there The reaction between the haloalkylated naphthois added dropwise with stirring a solution of 19.2 g. (0.12 quinone and the mercapto or mercapto-like compound mole) of potassium Xanthate in 500 ml. of alcohol. On

v) the following day the precipitated yellow product is filtered off with suction, Washed successively with alcohol, water and alcohol and allowed to dry. The product (15.3 g. of M.P. 109111 C.) is obtained analytically pure by recrystallizing once from thirty times its quantity of alcohol and then melts at 1l3114 C.

Example 3 To a mixture of 22.0 g. (0.1 mole) of 2-methyl-3- chloromethyl-1,4-naphthoquinone and 150 ml. of alcohol there is added dropwise with stirring a solution of 22.4 g. (0.1 mole) of potassium 0,0-diethyl-thiono-thiolphosphate in 150 ml. of alcohol. On the following day the precipitated potassium chloride is filtered off with suction and the filtrate is concentrated in a vacuum. The solid yellow residue is washed with water and subsequently with a little alcohol and after drying (32.5 g. of M.P. 69.5-71.5 C.) recrystallized from five times its quantity of alcohol (cooling to 20 C.). The product is then analytically pure and melts at 71-72 C.

Example 4 does not change upon recrystallization from ten times its quantity of alcohol.

Example 5 15.2 g. (0.2 mole) of thiourea are warmed in 300 ml. of alcohol until dissolved and 44.0 g. (0.2 mole) of Z-methyl 3 chloromethyl-l,4-naphthoquinone are then added and the mixture boiled up once more. The reaction product as formulated in the heading is precipitated, the mixture is allowed to cool by itself and the precipitate is filtered 01f with suction at 0 C. and washed with cold ethanol. The melting point of the dry compound (47.5 g.) lies at 193-195" C. (decomposition) after dipping at 180 C. It does not change upon recrystallization from fifteen times its quantity of methanol.

Example 6 M NH H NH 0 A solution of 51 g. (0.2 mole) of 2,3-bis-chloromethyl- 1,4-naphthoquinone in 2 liters of hot alcohol are treated with a solution of 33.5 g. (0.44 mole) of thiourea in 1 liter of alcohol. The product as formulated in the heading gradually precipitates. It is filtered oif with suction after a few days, washed with alcohol and dried. The yield amounts to 50 g.

To a suspension consisting of 22.0 g. (0.1 mole) of 2-methyl-3-chloromethyl-1,4-naphthoquinone and 300 ml. of methanol there is added dropwise with stirring a solution of potassium N,N-pentamethylene-dithiocarbamate, prepared from 0.1 mole of sodium methylate (in 46 m1. of methanolic solution), 9.9 ml. (0.1 mole) of piperidine and 6.7 ml. (0.11 mole) of carbon disulfide. The precipitated product, as formulated in the heading, is filtered off with suction after some time, washed with methanol, water and again with methanol. The dry product (30.5 g. of decomposition point 139-140 C.) is obtained analytically pure by reprecipitating once from chloroformmethanol; decomposition point 143 C.

Example 8 35.5 g. (0.1 mole) of 2,3-his-chloromethyl-1,4-naphthoquinone in 200 ml. of methanol are reacted with stirring with sodium N,N-pentamethylene-dithiocarbamate, prepared from 0.2 mole of sodium methylate (in 92 ml. of methanolic solution), 19.8 ml. (0.2 mole) of piperidine and 13.4 ml. (0.22 mole) of carbon disulfide. After some time the precipitated compound, as formulated in the heading, is filtered off with suction and washed with methanol, water and again with methanol. The air-dried yellow product (46.2 g. of decomposition point 125.5- 126.5 C.) is obtained analytically pure by reprecitating once from chloroform ethanol; decomposition point 129.5 C.

Example 9 55.8 grams (0.2 mole) of 2-methyl-3-(a-bromoethyl)- 1,4-naphthoquinone, 600 milliliters of alcohol and 53.7 grams (0.24 mole) of 0,0-diethyl-thionothiol phosphoric acid potassium salt were stirred together for four days. This is suction filtered at 0 C., washed with chilled alcohol, water and again with alcohol. The dried crude product (61 grams of M.P. 73-76" C.) was purified by recrystallization from a little alcohol. The compound then melts at 76.5-77 C.

tallizing it from methylethylketone. The decomposition point lies at 180.5181 C.

Example 11 o H U- CH S-fi-N N-OH3 Li S CH3 To a mixture of 33.0 grams (0.33 mole) of N-methylpiperazine and 300 milliliters of alcohol, there is added dropwise under ice cooling and stirring within thirty minutes 21.6 milliliters of carbon disulfide. Then this is mixed with an additional 500 milliliters of alcohol and there is gradually introduced under further ice cooling 66.0 grams (0.3 mole) of 2-methyl-3-chloromethyl-l,4- naphthoquinone. The yellow suspension is then stirred at room temperature for six days, suction filtered at 0 C. and washed with a little cool alcohol. The filter cake is mixed with 4 liters of Water and treated portionwise with 42 grams of sodium bicarbonate. The next day the crude product of the heading formula is suction filtered, washed with water, dried (62.5 grams) and purified by dissolving and reprecipitating from benzol-ether. Melting point 1l8119 C.

What is claimed is:

1. A compound of the formula:

in which R is selected from the group consisting of 6 and CH -S-fi-N N-OH3 s and R is selected from the group consisting of 10 CZHS C Hz-S-fi-( 0 2 5)z CHzSC-NHz CHz-S-C-N lg and OH--S|I|(0C2H5)2 13113 S R and R never both being CH 2. The compound 0 l ILCH;

CHgS-COC2H5 I] II S o 3. The compound CHgSC-O 021-15 l I 0HzSO C2115 o 4. The compound if I CH3 CHSGN g 5. The compound 0 s ours-Ji- I I OHPH O s 6. The compound l 0H S-C-N N- CH;

I l CH3 No references cited.

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, HENRY R. JILES, Examiners.

JOSE TOVAR, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA:
 6. THE COMPOUND 